We have brought together a group of scientists with wide experience in various aspects of antiviral therapy - from chemical synthesis, in vitro and animal testing, biochemical and pharmacological evaluations - up to phase 1-3 clinical trials. We will use novel approaches towards developing new chemicals, such as nucleoside analogues and polyoxometalates, and testing these drugs in various systems. It should then be possible to ascertain rapidly the potential of any compound developed by our group to be active and selective against HTLV-III/LAV and to determine under what circumstances it may be used to prevent or treat human HTLV-III/LAV infection. Elucidation of the mechanism of action of the compounds that are selective inhibitors of HTLV-III/LAV will be of immediate value in guiding the synthetic efforts. We will also attempt to characterize new enzymes induced by HTLV-III/LAV which may be potential targets for antiviral chemotherapy. This program will also address the problem of antiviral resistance and the use of combined chemotherapy. All compounds, such as the nucleoside analogue (CS-85) we recently synthesized, are first tested in vitro against HTLV-III/LAV by several assays. If found to be non-toxic in various human cell systems, they are evaluated also in mouse cell culture using an ecotopic retrovirus which affects the nervous system. The compounds are then tested in vivo in NIH Swiss newborn mice to ascertain the potential effect of the drug to prevent or treat the retrovirus infections, as well as to obtain further toxicity data. Promising drugs are studied also biochemically and pharmacologically. Innovative approaches, such as the newly developed system of human hepatic cell cultures to define drug metabolism and transport will be used. Also newly developed is a nerve cell culture system which allows the study in vitro of HTLV-III/LAV infection of human neurons and the possible axonal transport, not only of virus, but also of test drugs. The effect of new antiviral drugs on the immune system and their ability to prevent or eliminate latent virus will also be examined. Finally, the drugs will be tested in a primate model - rhesus monkeys infected with a mangabey retrovirus with several similarities to the human virus. Our group will thus be able to provide a comprehensive approach: synthesis of new anti-HTLV-III/LAV compounds; biochemical and pharmacological evaluations of the compounds; and determination of their selective antiviral activity in various cell culture and animal models. The preclinical information obtained will be crucial to determine the selective effectiveness of anti-HTLV-III/LAV drugs which can be applied to the prevention and/or treatment of HTLV-III/LAV infections in humans with their associated diseases.